Coronavirus disease 2019 (COVID-19) vaccines are very effective at protecting against severe disease and death. However, the impact of the vaccine used, viral variants, and host factors on disease severity remain poorly understood. Here we compared COVID-19 clinical presentations and outcomes in vaccinated and unvaccinated patients in Mexico City. From March to September 2021, clinical and demographic characteristics were obtained from 1,014 individuals with a documented SARS-CoV-2 infection, and viral variants were identified in a subset of 386 patients. We compared unvaccinated, partially vaccinated, and fully vaccinated patients, stratifying by age groups. We fitted multivariate statistical models to evaluate the impact of vaccination status, SARS-CoV-2 lineages, vaccine types, and clinical parameters. Most hospitalized patients were unvaccinated. In patients over 61 years old, mortality was significantly higher in unvaccinated compared to fully vaccinated individuals. In patients aged 31 to 60 years, vaccinated patients were more likely to be outpatients (46%) than unvaccinated individuals (6.1%). We found immune disease and age above 61 years old as risk factors. While fully vaccination was found as the most protective factor against in-hospital death. This study suggests that vaccination is essential to reduce mortality in a comorbid population such as that of Mexico.